Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R.China.
Department of Gastroenterology, The First People's Hospital of Jiujiang, Jiujiang, Jiangxi 332000, P.R.China.
Int J Mol Med. 2018 Sep;42(3):1716-1722. doi: 10.3892/ijmm.2018.3749. Epub 2018 Jun 29.
To date, aquaporin‑4 (AQP4) has been considered as a critical contributor to neuroinflammation, but little is known about the underlying mechanism. Previous studies have shown that a critical enzyme involved in the sphingomyelin cycle, sphingosine kinase 1 (SPHK1), is implicated in inflammatory processes and contributes to chronic neuroinflammation. The present study investigated the role of AQP4 in proinflammatory cytokine release from astrocytes, with an emphasis on the SPHK1/mitogen‑activated protein kinase (MAPK)/protein kinase B (AKT) pathway. Using primary cultures isolated from AQP4+/+ and AQP4‑/‑ embryos, the production of tumor necrosis factor‑α (TNF‑α)/interleukin‑6 (IL‑6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. The results showed increased secretion of TNF‑α/IL‑6 in the two groups following LPS treatment, but a significantly lower level was observed in the AQP4‑/‑ group compared with that in the AQP4+/+ group. Although upregulation of SPHK1 was detected in the two genotypes, only a mild increase in SPHK1 was found in the AQP4‑/‑ genotype. The phosphorylation of MAPK/AKT was also confirmed to be attenuated in the AQP4‑/‑ group, suggesting decreased MAPK/AKT signaling over time in AQP4‑/‑ astrocytes. Overall, the study findings demonstrated that AQP4 deficiency alleviates proinflammatory cytokine release from astrocytes, in association with the SPHK1/MAPK/AKT pathway. This data improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.
迄今为止，水通道蛋白 4（AQP4）已被认为是神经炎症的关键贡献者，但对于其潜在机制知之甚少。先前的研究表明，鞘氨醇激酶 1（SPHK1）是鞘磷脂循环中涉及炎症过程的关键酶，并且有助于慢性神经炎症。本研究探讨了 AQP4 在星形胶质细胞中促炎细胞因子释放中的作用，重点研究了 SPHK1/丝裂原活化蛋白激酶（MAPK）/蛋白激酶 B（AKT）通路。使用从 AQP4+/+和 AQP4-/-胚胎中分离的原代培养物，比较了星形胶质细胞受到脂多糖（LPS）刺激后肿瘤坏死因子-α（TNF-α）/白细胞介素-6（IL-6）的产生。结果显示，LPS 处理后两组 TNF-α/IL-6 的分泌均增加，但 AQP4-/-组明显低于 AQP4+/+组。尽管在两种基因型中均检测到 SPHK1 的上调，但仅在 AQP4-/-基因型中发现 SPHK1 的轻度增加。还证实 MAPK/AKT 的磷酸化在 AQP4-/-组中被减弱，表明 AQP4-/-星形胶质细胞中 MAPK/AKT 信号随时间减弱。总体而言，研究结果表明，AQP4 缺乏可减轻星形胶质细胞中促炎细胞因子的释放，与 SPHK1/MAPK/AKT 通路有关。该数据提高了我们对神经炎症事件中 AQP4 的认识，突出了 SPHK1 作为治疗中枢神经系统炎症的潜在靶点的新特征。
